The objective of this research is to identify the mechanisms supporting behavioral response inhibition in normal humans and those individuals with attention-deficit/hyperactivity disorder (ADHD). Response inhibition is a central element of the executive control of behavior. An essential feature of ADHD is an impairment of the ability to inhibit inappropriate responses. Understanding the brain signaling mechanisms and neurotransmitter systems underlying behavioral response inhibition is necessary to inform development of treatments for ADHD. There is behavioral, neuropharmacological, neurophysiological, and neuroanatomical evidence that the locus coeruleus norepinephrine (LC-NE) system is involved in response inhibition. The go/no-go and stop signal reaction time tasks have been used to examine the neuroanatomy, neuropharmacology, and neurophysiology underlying both response-restraint and response-cancellation behavior in humans, primates, and rats. We propose to perform neurophysiological recordings of neurons in rat LC to identify the patterns of activity associated with response inhibition under various conditions. In so doing, we will test the hypothesis that the phasic activity of LC neurons is necessary for response inhibition. Specific Aim 1) Determine the activity of LC neurons during response inhibition. Rats will be implanted with microelectrode arrays in LC, and we will record the activity of LC neurons while rats perform the two response inhibition tasks noted above. We will then analyze the activity of LC neurons during task performance to determine if they show phasic activity related to specific components of behavior. Specific Aim 2) Determine the effects of selective NE reuptake blockade on 1) response inhibition task performance and 2) the activity of LC and OFC neurons. We will record the activity of LC and OFC neurons simultaneously while rats perform response inhibition tasks after atomoxetine or saline administration. We will then analyze 1) specific components of rat behavior and 2) the activity of LC and OFC neurons during task performance to determine if either is altered by systemic atomoxetine administration. Specific Aim 3) Determine the effects of LC stimulation on response inhibition task performance. Rats will be implanted with microelectrodes in LC for recording and stimulation. During response inhibition task performance we will both record and periodically stimulate LC neurons to assess how LC stimulation affects behavioral performance. This work will provide valuable data to improve our understanding of response inhibition through novel analyses of the contribution of the LC-NE system to this behavioral model. The results of these studies will provide a novel contribution to the field and will assist in the design of targeted therapy for human disorders involving impaired response inhibition e.g., ADHD. PUBLIC HEALTH RELEVANCE: The objective of this research is to identify the mechanisms supporting behavioral response inhibition in normal humans and those individuals with attention-deficit/hyperactivity disorder (ADHD), as an essential feature of ADHD is an impairment of the ability to inhibit inappropriate responses. Understanding the brain signaling mechanisms and neurotransmitter systems underlying behavioral response inhibition is necessary to inform development of treatments for ADHD. This work will provide valuable data to improve our understanding of response inhibition through novel analyses of the contribution of the LC-NE system to response inhibition, and will assist in the design of targeted therapy for human disorders involving impaired response inhibition e.g., ADHD.